Receptor tyrosine kinase
Encyclopedia
Receptor tyrosine kinases (RTK)s are the high-affinity cell surface receptors for many polypeptide growth factor
s, cytokine
s, and hormone
s. Of the 90 unique tyrosine kinase gene
s identified in the human genome
, 58 encode receptor tyrosine kinase proteins.
Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer
.
, e.g., the insulin receptor
that forms disulfide-linked dimers in the absence of hormone; moreover, ligand binding to the extracellular domain induces formation of receptor dimers. Each monomer
has a single hydrophobic transmembrane-spanning domain
composed of 25-38 amino acid
s, an extracellular
N-terminal region, and an intracellular
C-terminal region. The extracellular N-terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellular ligands
, e.g., a particular growth factor
or hormone
. The intracellular C-terminal region displays the highest level of conservation and comprises catalytic domains responsible for the kinase
activity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates..
, a kinase is a type of enzyme
that transfers phosphate
groups (see below) from high-energy donor molecules, such as ATP
(see below) to specific target molecules (substrate
s); the process is termed phosphorylation
. The opposite, an enzyme that removes phosphate groups from targets, is known as a phosphatase
. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed tyrosine kinases.
When a growth factor binds to the extracellular domain of an RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellular tyrosine
residue
s.
residues within the activated receptor creates binding sites for Src homology 2
(SH2) domain- and phosphotyrosine binding (PTB) domain-containing proteins.
Specific proteins containing these domains include Src
and phospholipase C
γ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation of signal transduction
pathways. Other proteins that interact with the activated receptor act as adaptor protein
s and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstream signal transduction
pathways, such as the MAP kinase signalling cascade.
and Alzheimer's Disease
.
In mice, loss of signaling by any member of the ErbB family results in embryo
nic lethality with defects in organs including the lung
s, skin
, heart
, and brain
. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor
. ErbB-1 and ErbB-2 are found in many human cancer
s and their excessive signaling may be critical factors in the development and malignancy of these tumor
s.
s comprise the largest family of growth factor ligands at 23 members. The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR.
These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of three immunoglobulin (Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily
.
Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b.
A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2.
(VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).
The VEGF receptors have an extracellular portion consisting of seven Ig-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis
in response to VEGF-C and VEGF-D.
results in the production of 3 different isoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9 amino acid
s in their C-terminal tail, respectively. The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo, as these are the most common isoforms in which RET occurs.
RET is the receptor for members of the glial cell line-derived neurotrophic factor
(GDNF) family of extracellular signalling molecules or ligands
(GFLs).
In order to activate RET, first GFLs must form a complex
with a glycosylphosphatidylinositol (GPI)-anchored co-receptor
. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs.
Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine
residues within the tyrosine kinase
domain of each RET molecule. Phosphorylation
of these tyrosine
s then initiates intracellular signal transduction
processes.
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s, cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, and hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s. Of the 90 unique tyrosine kinase gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s identified in the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
, 58 encode receptor tyrosine kinase proteins.
Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Receptor tyrosine kinase classes
Approximately 20 different RTK classes have been identified.- RTK class I (EGF receptor familyErbBThe ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
)(ErbB family) - RTK class II (Insulin receptorInsulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
family) - RTK class IIIRTK class IIIRTK class III is a class of receptor tyrosine kinases.It includes C-KIT, C-FMS, and FLT3....
(PDGF receptorPlatelet-derived growth factor receptorPlatelet-derived growth factor receptors are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including...
family) - RTK class IV (FGF receptorFibroblast growth factor receptorThe fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions...
family) - RTK class V (VEGF receptorsVEGF receptorsVEGF receptors are receptors for vascular endothelial growth factor . There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound or soluble , depending on alternative splicing.-VEGF:...
family) - RTK class VI (HGF receptorC-METc-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity...
family) - RTK class VII (Trk receptorTrk receptorTrk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signal cascades...
family) - RTK class VIII (Eph receptorEph receptorEph receptors are components of cell signalling pathways involved in animal growth and development, forming the largest sub-family of receptor tyrosine kinases . The extracellular domain of an Eph receptor interacts with ephrin ligands, which may be tethered to neighbouring cells...
family) - RTK class IX (AXL receptorAXL receptor tyrosine kinaseTyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.-Interactions:AXL receptor tyrosine kinase has been shown to interact with TENC1.-Further reading:...
family) - RTK class X (LTK receptor family)
- RTK class XI (TIE receptorAngiopoietin Receptors: Tie-1 & Tie-2The angiopoietin receptors are receptors that bind angiopoietin.TIE-1 and TIE-2 comprise the cell-surface receptors that bind and are activated by the angiopoietins,...
family) - RTK class XII (ROR receptorReceptor tyrosine kinase-like orphan receptorIn the field of molecular biology, receptor tyrosine kinase-like orphan receptors are a family of tyrosine kinase receptors that are important in regulating skeletal and neuronal development, cell migration and cell polarity. ROR proteins can can modulate Wnt signaling by sequestering Wnt ligands....
family) - RTK class XIII (DDR receptorDDR1For the older type of computer memory, see DDR SDRAM.Discoidin domain receptor family, member 1, also known as DDR1 or CD167a , is a human gene.-Further reading:...
family) - RTK class XIV (RET receptorRET proto-oncogeneThe RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
family) - RTK class XV (KLG receptorPTK7Tyrosine-protein kinase-like 7 is an enzyme that in humans is encoded by the PTK7 gene.-Further reading:...
family) - RTK class XVI (RYK receptorRelated to receptor tyrosine kinaseThe related to receptor tyrosine kinase gene encodes the protein Ryk.-History:The gene encoding mouse RYK was first identified in 1992.Subsequently cDNA encoding the RYK protein have been isolated from the following species.*rat*chicken*Human...
family) - RTK class XVII (MuSK receptorMuSK proteinMuSK is a receptor tyrosine kinase required for the formation of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.-MuSK is required for formation of the Neuromuscular Junction:...
family)
Structure
Most RTKs are single subunit receptors but some exist as multimeric complexesProtein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
, e.g., the insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
that forms disulfide-linked dimers in the absence of hormone; moreover, ligand binding to the extracellular domain induces formation of receptor dimers. Each monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
has a single hydrophobic transmembrane-spanning domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
composed of 25-38 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, an extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
N-terminal region, and an intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
C-terminal region. The extracellular N-terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellular ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
, e.g., a particular growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
or hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
. The intracellular C-terminal region displays the highest level of conservation and comprises catalytic domains responsible for the kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates..
Kinase activity
In biochemistryBiochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, a kinase is a type of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that transfers phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
groups (see below) from high-energy donor molecules, such as ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(see below) to specific target molecules (substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
s); the process is termed phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. The opposite, an enzyme that removes phosphate groups from targets, is known as a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed tyrosine kinases.
When a growth factor binds to the extracellular domain of an RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellular tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residue
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
s.
Signal transduction
The phosphorylation of specific tyrosineTyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues within the activated receptor creates binding sites for Src homology 2
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
(SH2) domain- and phosphotyrosine binding (PTB) domain-containing proteins.
Specific proteins containing these domains include Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
and phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
γ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation of signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways. Other proteins that interact with the activated receptor act as adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstream signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways, such as the MAP kinase signalling cascade.
Epidermal growth factor receptor family
The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
In mice, loss of signaling by any member of the ErbB family results in embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic lethality with defects in organs including the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. ErbB-1 and ErbB-2 are found in many human cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s and their excessive signaling may be critical factors in the development and malignancy of these tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s.
Fibroblast growth factor receptor (FGFR) family
Fibroblast growth factorFibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
s comprise the largest family of growth factor ligands at 23 members. The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR.
These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of three immunoglobulin (Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily
Immunoglobulin superfamily
The immunoglobulin superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins ; they all possess a...
.
Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b.
A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2.
Vascular endothelial growth factor receptor (VEGFR) family
Vascular endothelial growth factorVascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).
The VEGF receptors have an extracellular portion consisting of seven Ig-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis
Lymphangiogenesis
Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis....
in response to VEGF-C and VEGF-D.
RET receptor family
The natural alternate splicing of the RET geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
results in the production of 3 different isoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s in their C-terminal tail, respectively. The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo, as these are the most common isoforms in which RET occurs.
RET is the receptor for members of the glial cell line-derived neurotrophic factor
Glial cell line-derived neurotrophic factor
Glial cell-derived neurotrophic factor, also known as GDNF is a protein that, in humans, is encoded by the GDNF gene.GDNF is a small protein that potently promotes the survival of many types of neurons.-Function:...
(GDNF) family of extracellular signalling molecules or ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
(GFLs).
In order to activate RET, first GFLs must form a complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
with a glycosylphosphatidylinositol (GPI)-anchored co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs.
Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues within the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain of each RET molecule. Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of these tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s then initiates intracellular signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
processes.
Eph receptor Family
Ephrin and Eph receptors are the largest subfamily of RTKs.See also
- Tyrosine kinaseTyrosine kinaseA tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
- Insulin receptorInsulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
- Enzyme-linked receptorEnzyme-linked receptorAn enzyme-linked receptor is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side.These are found in all living species....
- TyrphostinsTyrphostinsA tyrosine-kinase inhibitor is a pharmaceutical drug that inhibits tyrosine kinases, enzymes responsible for the activation of signal transduction cascades...
- Bcr-Abl tyrosine kinase inhibitors